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Bisphenol S (BPS), a safer alternative to bisphenol A, is commonly used as a plasticizer to manufacture various food-packaging materials. The accumulated BPS inhibits osteoblastic bone formation and promotes osteoclastogenesis, thereby accelerating remarkable bone destruction, but it is unclear whether BPS affects osteocytes, comprising over 95% of all bone cells. This study aimed to investigate the biological effect of BPS on osteocytes in vitro, as well as the detailed mechanism. Results showed that BPS (200, 400 μmol/L) exposure caused dose-dependently cell death of osteocytes MLO-Y4, and increased cell apoptosis. BPS induced loss of mitochondrial membrane potential (MMP) and mitochondria impairment. Furthermore, BPS upregulated expressions of mitophagy-related proteins including microtubule-associated protein light chain 3 (LC-3) II and PTEN-induced putative kinase (PINK) 1, accompanied by elevation of autophagy flux and the accumulation of acidic vacuoles; whereas p62 level was downregulated after BPS treatment. Additionally, BPS triggered the production of intracellular reactive oxygen species (ROS) and mitochondrial ROS (mtROS), while it decreased expression levels of nuclear factor E2-related factor 2 (Nrf2) and quinone oxidoreductase 1 (NQO1). The specific mtROS scavenger Mito-TEMPO reversed cell apoptosis and mitophagy, suggesting that mtROS contributes to BPS exposure-induced apoptosis and mitophagy in MLO-Y4 cells. Our data first provide novel evidence that apoptosis and mitophagy as cellular mechanisms for the toxic effect of BPS on osteocytes, thereby helping our understanding of the potential role of osteocytes in the adverse effect of BPS and its analogs on bone growth, and supporting strategies targeting bone destruction caused by BPS.

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